to waive or not to waive - health insight forum · ⇒a simple dissolution test (comparison) could...

TO WAIVE OR NOT TO WAIVE

SOULA KYRIACOS, PhDR&D Manager, PHARMALINE

April 2015

BIOWAIVER

Waiver of In Vivo BE Studies…Not waiver of BE!

Regulatory Bioequivalence:An Overview

What do we mean with equivalence ?Pharmaceutical equivalence

Bioequivalence

Regulatory Bioequivalence: An OverviewSometimes pharmaceutical equivalence is enough

Aqueous solutions– Intravenous solutions– Intramuscular, subcutaneous– Oral solutions– Optic or ophthalmic solutions– Topical solutions– Solutions for nasal administration

Powders for reconstitution as solution

Gases for inhalation

“Self-evident” - Biowaivers grantedCondition: excipients do not alter absorption / disposition /viscosity

Regulatory Bioequivalence: An Overview

Sometimes it is not enough

Pharmaceutical equivalence by itself doesnot necessarily imply therapeutic equivalence

Regulatory Bioequivalence: An OverviewMETHODS FOR DEMONSTRATING BE

• In vivo testing in humans, using a pharmacological response (pharmacodynamic endpoint)

• Well controlled clinical trials in humans that establish the safety and effectiveness of the drug product.

• An in vivo test in humans in which the concentration of the active ingredient or metabolite in an accessible biological fluid is measured as a function of time

• In vitro methods (e.g., dissolution)– BIOWAIVERS

BiowaiversBiowaivers are granted on the basis of:

• Composition Proportionality– based on:– acceptable BE studies on the highest strength– Proportional similarity of the formulations across all strengths

(Qualitatively same, Quantitatively proportional)– Manufactured by same manufacturing process– Acceptable in vitro dissolution testing of all strengths– Linear pharmacokinetics

• In Vivo In Vitro Correlation– Based on correlation between in vitro data and in vivo profile

• Biopharmaceutics Classification System – Considers the solubility, permeability and dissolution behaviour

Biowaivers and theBiopharmaceutics Classification System

BCS was introduced in 1995 by the US FDA

• First aim: granting biowaivers for Scale-Up and Post-Approval Changes (SUPAC).e.g. Changes in excipients, manufacturing site…

⇒A simple dissolution test (comparison) could be accepted as surrogate

• Second aim: more recently, extension of the BCS concept for approval of oral generic products.

BCS as a Prognostic tool in oral drug product development• Amidon GL et al. A theoretical basis for a biopharmaceutics drug

classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995: 12(3)

• FDA Guidance for industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, 2000.

BCS as Precursor classification tool for the BDDCS• Wu CY, Benet LZ. Predicting drug disposition via application of BCS:

transport/absorption/elimination interplay and development of a Biopharmaceutical Drug Disposition Classification System. Pharm Res. 2005: 22(1)


BCS - Prognostic tool in Oral drug product development:

• Identify the RLS in the intestinal absorption process

• Discovery and early development of NME

• BA/BE standards for IR oral drug product approval (FDA, EMA, WHO)– Waiver of In Vivo BE Studies– Objective of biowaivers: lower the regulatory burden without

loss of drug product quality


BCS as a precursor classification tool for BDDCS

• Drug disposition of NME

• Effects of efflux and absorptive transporters on oral absorption

• Food-drug effects

• Potential drug-drug interactions in the intestine and/or liver


Biopharmaceutics classification system –Scientific Rationale

Fundamental parameters controlling oral drug absorption, Amidonet al (1995): Permeability of the drug through GI membraneSolubility/dissolution of the drug dose in the GI milieu

Objective: Predict in vivo pharmacokinetic performance of drug products


BCS takes a mechanistic approach to setting BE standards: mass transport in the GI tract

Amidon, 1995


• If two drug products containing the same drug, have the same concentration time profile at the intestinal membrane surface, then they will have the same rate and extent of absorption.

⇒ if two drug products have the same in vivo dissolution profile under all luminal conditions, they will have the same rate and extent of drug absorption.


The science of BE is at the absorption site

Similar in vivo dissolution → similar plasma levelsIn vitro dissolution → in vivo dissolution

Note: • In Vitro dissolution methodology must capture the most important rate

controlling in vivo dissolution process• Post-absorption events (MTB, enterohepatic recycling) can result in complex

and variable pharmacokinetic profiles – with little relevance to drug product quality /BE.

• 60% of HVDs – highly variable due to drug substance PK characteristics rather than drug product characteristics (AAPS J, 2008)


Biopharmaceutics classification system

• Scientific framework which divides APIs into four groups, according to their solubility and their permeability properties. (Amidon et al., 1995)

High Solubility Low Solubility

High

Per

mea

bilit

y Class 1High solubilityHigh permeability

IVIVC if dissolution rate < GE rate

Class 2Low solubilityHigh permeability

IVIVC if in vitro dissolution rate ∼ in vivo dissolution rate

Low

Per

mea

bilit

y Class 3High solubilityLow permeability

Limited or no IVIVC

Class 4Low solubilityLow permeability

Limited or no IVIVC

Biopharmaceutics classification system Eligibility criteria for biowaiver - Oral generic drugs

BCS classification of the API: solubility and permeability Dissolution characteristics Nature of the excipients - may influence motility and/or

permeability in the gastrointestinal tract. Therapeutic Index Formulation: product not designed to be absorbed from the

oral cavity and not MR Risk assessment: To be performed only if an incorrect

biowaiver decision is likely to create a risk for the patient


BCS classification of the API: solubility and permeability

Class 1Highly permeable

Highly soluble

Class 3Poorly permeable

Highly soluble


Poorly soluble


Poorly soluble

BCS classification of the API: solubility and permeability

• High Solubility– the highest dose strength is soluble in <250 mL aqueous buffers over

pH range of at 37oC. pH range of 1-7.5 at 37 ± 1 °C (FDA)pH range of 1-6.8 at 37 ± 1 °C (EMA)pH range of 1.2-6.8 at 37 ± 1 °C (WHO)

• High Permeability– Pharmacokinetic Studies in Human:

• Mass Balance Studies• Absolute BA Studies - extent of absorption in humans is determined to be ≥ 90% (FDA), ≥ 85% (EMA, WHO)

– Intestinal Permeability Methods• monolayers of suitable epithelial cells , e.g. Caco-2 cell line



Highly soluble


-Eligible for biowaivers, FDA, EMA, WHO

Excipient / extent of BA-FDA: qty consistent with intended function-EMA: Excipients that might affect BA are qualitatively and quantitatively the same.

Transportereffects minimal


Poorly soluble

Eligible for Biowaivers(WHO):-dose: solubility ratio <250ml at pH 6.8-Rapidly dissolving ≥ 85% in 30 min (pH 6.8)-Similar dissolution profile vs comparator (pH 1.2, 4.5, 6.8)

Oral availability of the API depends on the formulation and manufacturing method


Efflux transporter effectspredominate


Highly soluble

Eligible for biowaivers (EMA, WHO)

- Product is very rapidly dissolving - Excipient effects on uptake transportersExcipients that might affect BA are qualitatively and quantitatively the sameAND other excipients are qualitatively the same and quantitatively very similar.

Biopharmaceutics classification system Absorptive transporter effects predominate


Poorly soluble

-Not eligible for biowaivers

-BA is minimal


Absorptive andEfflux transporterEffects could beimportant

DISSOLUTION TESTING: SOUL OF BIOWAIVERS

• Different from compendial testing– Media: 900mL: pH 1-1.2, 4.5, 6.8– Number of units tested: 12

• Minimum 3 time-points for both profiles• Sampling schedule: 10, 15, 20, 30 and 45 min• Apparatus: Rotating basket (100 rpm), rotating paddle (50 rpm)• Comparative dissolution profile• Acceptance criteria:

Class 1: very rapid (> 85 % within 15 min) or similarly rapid (85 % within 30 min)Class 3: very rapid (> 85 % within 15 min)

The Biowaiver Monographs • An initiative of the Federation Internationale Pharmaceutique (FIP).

• The aim is to evaluate all relevant data from the literature, for a given API, to assess the risk associated with a biowaiver– RISK = probability of an incorrect biowaiver decision– RISK = consequences of an incorrect biowaiver decision in terms of

public heath and individual patient risks. – RECOMMENDATION = Biowaiver

• No formal regulatory status but represents the best current scientific opinions

• The approach includes all factors considered in the WHO Document:„Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms.”Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations

The Biowaiver MonographWhat is taken into consideration?

The Biowaiver MonographEvaluation of the collected information

Prof. Dr. Jennifer Dressman & Corina Becker, 2007

Biowaiver Monographs already available• Acetaminophen = Paracetamol Acetazolamide• Acetylsalicylic acid Aciclovir• Amitriptyline Hydrochloride Amodiaquine Hydrochloride• Atenolol Bisoprolol fumarate• Chloroquine Phosphate Chloroquine Sulfate• Chloroquine Hydrochloride Cimetidine• Ciprofloxacin Hydrochloride Codeine phosphate• Diclofenac Potassium Diclofenac Sodium• Doxycycline Hyclate Efavirenz• Ethambutol Dihydrochloride Fluconazole• Furosemide Ibuprofen• Isoniazid Ketoprofen• Lamivudine Levetiracetam• Levofloxacin Mefloquine Hydrochloride• Metoclopramide Hydrochloride Metronidazole• Piroxicam Prednisolone • Prednisone Primaquine Diphosphate• Propranolol Hydrochloride Pyrazinamide • Quinidine Sulfate Quinine Sulfate • Ranitidine Hydrochloride Rifampicin • Stavudine Verapamil Hydrochloride• Zidovudine (Azidothymidine)

www.fip.org/bc

Biowaiver monograph

J Pharm Science

Additional source for BCS classification

• Therapeutic Systems research Laboratory (TSRL Inc., Ann Arbor, MI) http://www.tsrlinc.com/services/bcs/search.cfm)

A decade of biowaivers - FACTS

• No incidents of Type I errors in the use of in vitro testing to assess BE of Class 1 drugs in the USA and EU. (Mehta 2002, 2007)

• Clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test (Dahan et al, AAPS J. 2009)

Conclusion

Biowaivers– Based on scientific principles– Avoid unnecessary human experiments– Reduce cost and time of developing generic IR oral drug

products– Enhance the efficiency in drug development and regulatory

approval processes– BCS provides an invaluable tool in drug discovery,

development, and regulation.

Challenges

• Barriers that limit biowaiver application– Lack of international regulatory harmonization– Uncertainty in regulatory approval– Organizational barriers

• New regulatory policies, with criteria and class boundaries that will allow granting an in vivo biowaiver to larger number of drugs.

THANK YOU

to waive or not to waive - health insight forum · ⇒a simple dissolution test (comparison) could...

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